FDG-PET of mouse breast cancers on ketogenic vs. standard chow diets, with or without added rapamycin.

280 Objectives: Prior pilot studies have shown that ketogenic diets may stabilize PET 18F-FDG markers of progression in advanced cancers (1) without unsafe adverse effects and can inhibit cancer growth in vitro without adversely affecting normal cells(2). A ketogenic diet (KD) vs. a standard chow diet (SD), each with or without supplemental oral rapamycin (Rapa), were provided to mice in a model of breast cancer. The goal was to compare potential effects on PET-FDG uptake. Insulin inhibition, as is seen on a KD, can interfere with mTOR and other signaling molecules of growth and resistance to apoptosis within cancer cells. Further, ketone bodies have been demonstrated to have histone deacetylase inhibitor activity. We hypothesized that insulin inhibition due to carbohydrate restriction, as well as ketosis, would slow tumor growth vs. a standard diet. We also hypothesized that added rapamycin would have a synergistic effect on tumor inhibition. Synergies of KD with PI3K inhibitors in mouse models of cancer have also recently been published (3). Methods: Mice with spontaneous breast cancers (transgenic mouse strain FVB/N-Tg (MMTV-PyVT) 634Mul/J), at 6 weeks of life, were begun on either a KD (<1% carbohydrate-CHO) vs. SD (55% CHO) (n=3 mice each), all with 10% protein. Additional groups of mice (n=3) on KD as well as SD were also assigned to supplemental Rapa 0.4 mM and 4 mM. Mice were imaged at 35 days after arrival, when tumors were palpable. Imaging was performed after injection of 100 uCi 18F-FDG on a Siemens Inveon MicroPET scanner. Breast tumor regions of interest (ROI’s) were drawn manually, and parameters measured were total breast tumor volume (TV) and total glycolytic volume (GV). GV was calculated = mean SUV x TV. Tumor volume was obtained solely for the purpose of calculating GV. Results: Total tumor Glycolytic Volume (2857ul) on a KD was substantially and significantly (p<0.001) lower than the respective value for mice on a SD (7818ul). In mice with added rapamycin therapy, the GV for KD + R 0.4 mM was 2812ul, not significantly different from the KD without R; while the SD + R showed reduction in GV to 3005ul (from 7818ul). On 4 mM R, total GV for mice on the KD +R was 2233ul compared to GV for SD +R at 1930ul. Conclusions: A ketogenic diet reduces the rate of tumor growth in mice with spontaneous breast tumors compared with standard mouse chow, as hypothesized. Adding orally ingested rapamycin further slowed growth rates of both groups, but differences due to the diets vanished. Rapamycin dominates the cancer inhibiting effects on glycolytic volume when added to a ketogenic diet as measured on 18F-FDG PET FDG scans.